HIV Infections
Conditions
Brief summary
The purpose of this study was to determine the dosage for oral cabotegravir (CAB) and long-acting cabotegravir (CAB LA) and long-acting rilpiverine (RPV LA) and evaluate the safety, acceptability, tolerability, and pharmacokinetics (PK) of oral CAB, CAB LA, and RPV LA in virologically suppressed children and adolescents living with HIV.
Detailed description
IMPAACT 2017 was a Phase I/II, multi-center, open-label, non-comparative dose-finding study with the primary objective of evaluating the safety, acceptability, tolerability, and PK of oral cabotegravir (CAB) and long-acting cabotegravir (CAB LA) as well as long-acting rilpivirine (RPV LA) in adolescents living with HIV-1, who are 12 to \<18 years of age, ≥35kg, and virologically suppressed. The study design included two cohorts of participants and five study steps. In Cohort 1, Step 1 participants received either oral CAB or oral rilpivirine (RPV) for at least four weeks and up to six weeks (maximum). In Cohort 1, Step 2 participants received intramuscular injectable formulations of the study products, either CAB LA or RPV LA. Cohort 1 participants were assigned either CAB (Cohort 1C) or RPV (Cohort 1R) based on their pre-study combination Antiretroviral Therapy (cART) regimen. Participants on a PI-based and/or NNRTI-based cART regimen were assigned to Cohort 1C, and participants on a non-boosted INSTI-based cART regimen were assigned to Cohort 1R. All participants continued their pre-study cART regimen during Cohort 1. During Cohort 2, all participants discontinued their pre-study cART regimen and received both study products, CAB and RPV, at the doses established in Cohort 1. Cohort 2 participants enrolled to either Cohort 2A to receive both oral CAB + oral RPV (Step 3) followed by both CAB LA + RPV LA (Step 4) or Cohort 2B to directly receive both CAB LA + RPV LA without an oral lead-in phase (Step 5). If eligible, Cohort 1 participants were able to enroll into Cohort 2 (i.e., Cohort 1 Rollover). However, Cohort 2 participants who were not previously enrolled in Cohort 1 (i.e., Cohort 1-Naïve) were the primary group for analyses and conclusions. No participants enrolled into Cohort 2B, direct to injection (Step 5). Therefore, all references to Cohort 2 refer to Cohort 2A (Steps 3 and 4). Two interim analyses were planned. The first interim analysis established the doses for Cohort 2 and determined whether to open Cohort 2 to Cohort 1 participants who met criteria to enter Cohort 2. The second interim analysis provided justification to open Cohort 2 to additional participants who were not previously enrolled in Cohort 1. A final analysis of Cohort 1 data was performed to confirm the final doses for Cohort 2. Safety and PK evaluations were performed during Steps 1-5 and long-term safety follow-up (LSFU). Antiviral activity assessments were performed during Steps 1-5. Acceptability and tolerability were assessed during Steps 1-5 and LSFU, with all participants completing quantitative questionnaires and a subset of participants completing in-depth qualitative interviews. Additionally, parents/caregivers of a subset of U.S. participants from U.S. sites were also enrolled to complete a single in-depth qualitative interview. Because objectives related to parents/caregivers were exploratory, these outcomes are not described here. Cohort 1 participants were followed for up to 64 weeks. Participants were followed for at least four weeks in Step 1 (oral phase) and at least 12 weeks in Step 2 (injection phase). All Step 2 participants were followed (on cART, off study product) for up to an additional 48 weeks as part of LSFU after their last study product injection. If eligible, Cohort 1 participants enrolled into Cohort 2 before completing LSFU. For Cohort 1, Step 1 participants not progressing to Step 2, the last visit was targeted to be completed 28 days after the participant's last oral study product use. Cohort 2 participants were followed for up to 188 (Cohort 2B) or 192 (Cohort 2A) weeks. Participants were followed for at least four weeks in Step 3 (oral phase) and 92 weeks in Step 4/Step 5 (injection phase). After completing 92 weeks of follow-up in Step 4/Step 5 (injection phase), Cohort 2 participants who continued access to injectable study products through a mechanism external to the protocol exited the study. If it was not possible for participants to access injections of CAB LA + RPV LA from non-study sources at the completion of their Step 4 Week 96 or Step 5 Week 92 visit, participants remained in the study safety extension for up to 48 weeks. Participants who permanently discontinued injectable study product use during Cohort 2, Step 4/Step 5, or did not wish to continue to access the study products through the external mechanism after their Week 96 visit, were followed (on cART, off study product) for an additional 48 weeks as part of LSFU after their last study product injection, except for participants in the study safety extension. Participants in the study safety extension who decided to permanently discontinue injectable study product or who had not established access to study product after the 48 weeks in the study safety extension would exit the study (not enter LSFU). For Cohort 2, Step 3 participants not progressing to the injection phase, the last visit was targeted to be completed 28 days after the participant's last oral study product use. Female participants who discontinued study product use (either oral or injectable study product) due to pregnancy during Steps 1-5 were followed for an additional 48 weeks in LSFU to assess long-term safety and washout PK of the study products, except for participants in the study safety extension. Participants who became pregnant during the safety extension were only followed until the pregnancy outcome was determined.
Interventions
30 mg tablets administered orally
DRUGOral Rilpivirine (RPV)
25 mg tablets administered orally
Administered by intramuscular (IM) injection
DRUGLong-Acting Injectable Rilpivirine (RPV LA)
Administered by intramuscular (IM) injection
Participants continued their pre-study cART regimen. The antiretroviral drugs in participants' cART regimens were not provided through the study.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
ViiV Healthcare
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Cohort 1 Step 1, Cohort 2 Step 3, and Cohort 2 Step 5 All the following criteria must be met for inclusion of any adolescent participant in Step 1 of Cohort 1, or in Step 3 of Cohort 2, unless otherwise noted: * At enrollment, body weight greater than or equal to 35 kg (77 lbs) * Note: For Cohort 1 Step 2 participants, body weight will not be exclusionary for enrollment into Cohort 2 Step 3, if otherwise eligible. * For Cohort 1, at enrollment, body mass index (BMI) less than or equal to 31.5 kg/m\^2 * At enrollment, willing and able to comply with the study visit schedule and other study requirements, as determined by the site investigator or designee * Confirmed HIV-1-infection based on documented testing of two samples collected at different time points. More information on this criterion can be found in the protocol. * For at least 3 consecutive months (defined as 90 consecutive days) prior to screening, and prior to enrollment, has been on stable unchanged cART consisting of 2 or more drugs from 2 or more classes of antiretroviral drugs, ascertainment of this criterion may be based on parent or guardian report only, but available medical records should also be reviewed in relation to this criterion. * Note: Participants undergoing dose modifications to their antiretroviral regimen for growth or who are switching medication formulation(s) are considered to be on a stable cART. * Has at least one documented plasma HIV-1 RNA less than the lower limit of detection of the assay from a specimen collected 6 to 12 months (defined as 180 to 365 days) prior to entry. OR Has at least one documented plasma HIV-1 RNA less than the lower limit of detection of the assay from a specimen collected less than 6 months (defined as within 179 days) prior to entry and at least one documented plasma HIV-1 RNA result less than the lower limit of detection of the assay from a specimen collected in the 12-18 months (defined as 365 to 545 days) prior to entry. OR For Cohort 1 participants enrolling to Cohort 2, has documented plasma HIV-1 RNA results less than the lower limit of detection of the assay from all indicated Cohort 1 study visits with their Cohort 1 Week 16 visit completed within 28 days prior to Cohort 2 entry. * At screening, has Grade 2 or lower of all the following laboratory test results: * Alanine transaminase (ALT) (u/l) * Lipase (u/l) * Estimated creatinine clearance (CrCl; Schwartz formula mL/min/1.73m\^2) * Platelets (cells/mm\^3) * Hemoglobin (g/dL) * AST (u/l) * Absolute Neutrophil Count (cells/mm3) * See study protocol for guidance on severity grading. Laboratory tests may be repeated during the study screening period, with the latest result used for eligibility determination. * At screening, is on an atazanavir-containing (ATV) cART regimen, and has total bilirubin less than or equal to 1.5 mg/dL or normal direct bilirubin * At screening, has documented plasma HIV-1 RNA less than 50 copies/mL * At screening, mean value of Q-T interval (QTc) interval (automated machine readout or calculated using either Bazett or Fredericia) on ECG performed in triplicate, less than or equal to 500 msec. * For females, has a negative (blood or urine) human chorionic gonadotropin (hCG) laboratory test result at entry * For females of childbearing potential, at entry, currently using at least one allowable effective method of contraception, and agrees to use at least one allowable effective method of contraception throughout study participation, for at least 30 days after discontinuation of oral study product, and for at least 48 weeks after discontinuation of CAB LA and/or RPV LA, and intending to delay any planned pregnancies until 30 days after last oral study product use or until 48 weeks after last injectable study product use. * Note: See study protocol for details regarding contraceptive counseling, a list of the allowed effective contraceptive methods for this study, and the definition of a female of childbearing potential. Hormonal-based contraceptives must have been initiated within the prescribed time, per the respective contraceptive method, to be considered effective at the time of Entry. The site IoR or designee is responsible for ensuring that the contraceptive is used in accordance with the approved product label, and counseling participants on proper use of chosen methods of contraception, including barrier methods. * For Cohort 1 participants enrolling to Cohort 2, have completed all scheduled product injections and completed Week 16 visit in Cohort 1 Step 2
Exclusion criteria
Cohort 1 Step 1, Cohort 2 Step 3, or Cohort 2 Step 5 Adolescents will be excluded from the study if any of the following are identified during the screening period: * Within 6 months (defined as within 179 days) prior to entry, two consecutive documented HIV-1 RNA values greater than the lower limit of detection of the assay * Note: Unconfirmed virologic HIV-1 RNA value of greater than the lower limit of detection of the assay (transient detectable viremia, or "blip") prior to screening is not exclusionary. * For Cohort 1 participants enrolling to Cohort 2, Step 3, occurrence of any Grade 3 or higher adverse event assessed as related to study product or permanent discontinuation of study product due to an adverse event of any grade assessed as related to study product during participation in Cohort 1 (including any long-term safety and washout PK follow-up visits). * For participants enrolling to Cohort 1 Step 1, based on available medical records, currently on either a cART regimen containing both a protease inhibitor (PI) and an integrase strand transfer inhibitor (INSTI), or a cART regimen containing both an INSTI and a non-nucleoside reverse transcriptase inhibitor (NNRTI). * As determined by the IoR or designee, and based on available medical records, known or suspected resistance to RPV * As determined by the IoR or designee based on available medical records, known or suspected resistance to INSTIs * History of congestive heart failure, symptomatic arrhythmia, or any clinically significant cardiac disease, as determined by the IoR or designee based on available medical records * At entry, known active tuberculosis infection, requiring anti-tuberculosis treatment, as determined by the IoR or designee based on available medical records * Known hepatitis B or hepatitis C infection, as determined by the IoR or designee based on available medical records * Clinically significant hepatic disease, as determined by the IoR or designee based on available medical records * Current or anticipated need for chronic anti-coagulation, as determined by the IoR or designee, based on available medical records * History of sensitivity to heparin or heparin-induced thrombocytopenia, as determined by the IoR or designee, based on available medical records * History of known or suspected bleeding disorder including history of prolonged bleeding, as determined by the IoR or designee, based on available medical records * Known or suspected allergy to study product components * More than one seizure within one year (defined as within 365 days) prior to entry, or unstable or poorly controlled seizure disorder, as determined by the IoR or designee, based on available medical records. * At entry, participant is receiving (or has received in the last 7 days) any disallowed medication listed in the study protocol. * Current inflammatory skin condition that compromises the safety of intramuscular injections as determined by the IoR or designee. * Has a tattoo or other dermatological condition overlying the buttock region which, in the opinion of the IoR or designee, may interfere with interpretation of injection site reactions * Surgically-placed, or planned, buttock implants, per self-report * For females, lactating (per self-report and/or parent/guardian report) at entry * Enrolled in another clinical trial of an investigational agent, device, or vaccine * Any other condition or social circumstance situation that, in the opinion of the IoR or designee, would make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Had Grade 3 or Higher Adverse Event (Cohort 1) | Cohort 1 Treatment Initiation through Week 4 | Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 1) | Cohort 1 Treatment Initiation through Week 4 | Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE assessed as related by the site investigator of record to study product through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Had Serious Adverse Events Meeting International Conference on Harmonisation (ICH) Criteria Assessed as Related to Study Product/s (Cohort 1) | Cohort 1 Treatment Initiation through Week 4 | Adverse events (AE) were assessed as a Serious AE by ICH criteria. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details). We present the proportion of participants with at least one serious AE assessed as related to study product by the site investigator of record through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1) | Cohort 1 Treatment Initiation through Week 4 | We present the proportion of participants who permanently discontinued study product due to adverse events (AEs) assessed as related to study product by the site investigator of record through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1) | Cohort 1 Treatment Initiation through Week 4 | We present the proportion of participants who died due to adverse events assessed as related to study product by the site investigator of record through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q4W) | Week 4b, Week 8, Week 12 | We present the geometric mean pre-dose concentrations of each injection and associated geometric coefficient of variation for participants on the Q4W dosing regimen, based on analysis of pre-dose PK samples. |
| Proportion of Participants Who Had Grade 3 or Higher Adverse Events (Cohort 1) | Cohort 1 Treatment Initiation through Week 16 | Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Had Grade 3 or Higher Adverse Events (Cohort 2) | Cohort 2 Treatment Initiation through Week 24 | Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 2) | Cohort 2 Treatment Initiation through Week 24 | Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Had Serious Adverse Events Meeting ICH Criteria Assessed as Related to Study Product/s (Cohort 2) | Cohort 2 Treatment Initiation through Week 24 | Adverse events (AE) were assessed as a Serious AE by ICH criteria. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details). We present the proportion of participants with at least one serious AE assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2) | Cohort 2 Treatment Initiation through Week 24 | We present the proportion of participants who permanently discontinued study product due to adverse events (AEs) assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2) | Cohort 2 Treatment Initiation through Week 24 | We present the proportion of participants who died due to adverse events assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Geometric Mean Area Under the Plasma Concentration-time Curve (AUC) for Step 1 Oral CAB (Cohort 1C) | Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8, and (for Q4W dosing) 24 hours post-dose | AUC calculated using non-compartmental methods with linear up-log down trapezoidal rule (Phoenix WinNonlin v 8.3, Certara®). We present the geometric mean of the AUC with associated geometric coefficient of variation. |
| Apparent Total Body Clearance (CL/F) of Step 1 Oral CAB (Cohort 1C) | Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8 and (for Q4W dosing) 24 hours post-dose | We present the geometric mean of the total body clearance of CAB and associated geometric coefficient of variation, based on analysis of intensive pharmacokinetic (PK) samples. |
| Geometric Mean Maximum Plasma Concentration (Cmax) of Oral CAB (Cohort 1C) | Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8 and (for Q4W dosing) 24 hours post-dose | We present the geometric mean of the maximum plasma concentration of CAB and associated geometric coefficient of variation, based on analysis of intensive PK samples |
| Time of Maximum Concentration (Tmax) of Oral CAB (Cohort 1C) | Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8, and (for Q4W dosing) 24 hours post-dose | We present the mean time of maximum concentration of CAB and associated standard deviation, based on analysis of intensive PK samples. |
| Geometric Mean Pre-dose Concentration (C0) of Oral CAB (Cohort 1C) | Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8, and (for Q4W dosing) 24 hours post-dose | We present the geometric mean pre-dose CAB concentration and associated geometric coefficient of variation, based on analysis of intensive PK samples. |
| Geometric Mean Concentration of LA CAB/LA RPV at Week 16 (Cohort 1 Q4W) | Week 16 | We present the geometric mean concentration of LA CAB/LA RPV and associated geometric coefficients of variation for participants on the Q4W dosing regimen, based on analysis of pre-dose PK sample. |
| Geometric Mean Maximum Plasma Concentration (Cmax) of LA CAB/LA RPV (Cohort 1 Q4W) | Samples collected at Weeks 4b, 5, 6, and 8 | We present the geometric mean of the maximum plasma concentration of LA CAB/LA RPV and associated geometric coefficient of variation for the first injection in participants on the Q4W dosing regimen, based on analysis of intensive PK samples. |
| Time of Maximum Concentration (Tmax) of LA CAB/LA RPV (Cohort 1 Q4W) | Samples collected at Weeks 4b, 5, 6, 8 | We present the mean time of maximum concentration of LA CAB/LA RPV at the first injection and associated standard deviation for participants on the Q4W dosing regimen, based on analysis of intensive PK samples. |
| Geometric Mean Concentration of LA CAB/LA RPV at Week 16 (Cohort 1 Q8W) | Week 16 | We present the geometric mean concentration of LA CAB/LA RPV and associated geometric coefficients of variation for participants on the Q4W dosing regimen, based on analysis of the pre-dose PK sample. |
| Geometric Mean Maximum Plasma Concentration (Cmax) of LA CAB/LA RPV (Cohort 1 Q8W) | Samples collected at Weeks 4b, 5, and 8 | We present the geometric mean of the maximum plasma concentration of LA CAB/LA RPV and associated geometric coefficient of variation for the first injection in participants on the Q8W dosing regimen, based on analysis of intensive PK samples. |
| Time of Maximum Concentration (Tmax) of LA CAB/LA RPV (Cohort 1 Q8W) | Samples collected at Weeks 4b, 5, and 8 | We present the mean time of maximum concentration of LA CAB/LA RPV at the first injection and associated standard deviation for participants on the Q8W dosing regimen, based on analysis of intensive PK samples. |
| Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q8W) | Week 4b, Week 8 | We present the geometric mean pre-dose concentration of the first injection and associated geometric coefficient of variation for participants on the Q4W dosing regimen, based on analysis of pre-dose PK samples. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With HIV-1 RNA < 50 Copies/mL (Cohort 1) | Week 16 | We present the proportion of participants with results of HIV-1 RNA \< 50 copies/mL at Week 16 |
| Proportion of Participants Who Reported "Hurts Whole Lot" or "Hurts Worst" in Regards to Being Bothered by Pain During Injection of CAB LA or RPV LA (Cohort 1) | Week 8 | Results collected via administration of Pain During Injection survey to participants after receiving injection. Pain during injections was assessed using the Faces Pain Scale-Revised which includes 6 visual and text options: "no hurt," "hurts little bit," "hurts little more," "hurts even more," "hurts whole lot" and "hurts worst". |
| Median Dimension of Quality of Life Scores | Week 16 | A commonly used 23-item Pediatric Quality of Life Inventory, the PedsQLTM, was used to measure physical, emotional, and social dimensions of health as well as school functioning. Question responses were used to generate scores from 0-100 (100 being the best quality of life) based on the PedsQLTM guidelines. The number of participants drops slightly for the school functioning result as not all participants are eligible to answer these school-related questions. |
| Proportion of Participants Who Had Grade 3 or Higher Adverse Events (Cohort 2) | Cohort 2 treatment initiation through Week 48 | Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 48 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 2) | Cohort 2 treatment initiation through Week 48 | Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE assessed as related to study product by the site investigator of record through 48 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Had Serious Adverse Events Meeting ICH Criteria, as Cited in References, Assessed as Related to Study Product/s (Cohort 2) | Cohort 2 treatment initiation through Week 48 | Adverse events (AE) were assessed as a Serious AE by ICH criteria. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details). We present the proportion of participants with at least one serious AE assessed as related to study product by the site investigator of record through 48 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2) | Cohort 2 treatment initiation through Week 48 | We present the proportion of participants who permanently discontinued study product due to adverse events (AEs) assessed as related to study product by the site investigator of record through 48 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2) | Cohort 2 treatment initiation through Week 48 | We present the proportion of participants who died due to adverse events assessed as related to study product by the site investigator of record through 48 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI). |
| Proportion of Participants With Plasma HIV-1 RNA >= 50 Copies/mL Per the FDA Snapshot (Cohort 2) | Week 24 | We present the proportion of participants with HIV-1 RNA \>= 50 copies/mL and associated exact 95% CI (Clopper-Pearson) per the FDA snapshot, based on laboratory evaluations. |
| Proportion of Participants With Plasma HIV-1 RNA >= 200 Copies/mL Per the FDA Snapshot (Cohort 2) | Week 24 | We present the proportion of participants with HIV-1 RNA \>= 200 copies/mL and associated exact 95% CI (Clopper-Pearson) per the FDA snapshot, based on laboratory evaluations. |
| Geometric Mean Pre-dose Concentration (C0) of Oral CAB and Oral RPV (Cohort 2) | Week 2 | We present the geometric mean of the pre-dose concentration of oral CAB and oral RPV and associated coefficient of variation, based on analysis of pre-dose PK sample. |
| Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 24: Pre-dose CAB and RPV Concentrations at Week 8 (Cohort 2) | Week 8 and Week 24 | We present the geometric mean of the ratios of pre-dose CAB and RPV concentrations at Week 24:Week 8 and associated coefficient of variation, based on analysis of pre-dose PK samples. |
| Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 24: Pre-dose CAB and RPV Concentrations at Week 16 (Cohort 2) | Week 16 and Week 24 | We present the geometric mean of the ratios of pre-dose CAB and RPV concentrations at Week 24:Week 16 and associated coefficient of variation, based on analysis of pre-dose PK samples. |
| Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 48: Pre-dose CAB and RPV Concentrations at Week 8 (Cohort 2) | Week 8 and Week 48 | We present the geometric mean of the ratios of pre-dose CAB and RPV concentrations at Week 48:Week 8 and associated coefficient of variation, based on analysis of pre-dose PK samples. |
| Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 48: Pre-dose CAB and RPV Concentrations at Week 16 (Cohort 2) | Week 16 and Week 48 | We present the geometric mean of the ratios of pre-dose CAB and RPV concentrations at Week 48:Week 16 and associated coefficient of variation, based on analysis of pre-dose PK samples. |
Countries
Botswana, South Africa, Thailand, Uganda, United States
Contacts
STUDY_CHAIRCarolyn Bolton Moore, MSc, MBBCh
Centre for Infectious Disease Research in Zambia/University of Alabama Birmingham
STUDY_CHAIRAditya H. Gaur, MD
St. Jude Children's Research Hospital
Participant flow
Recruitment details
Accrual for Cohort 1 occurred between April 2019 and November 2021 at 15 different medical clinic sites across Botswana, South Africa, Thailand, and the United States. Accrual for Cohort 2 occurred between July 2021 and August 2022 at 18 different medical clinic sites across Botswana, South Africa, Thailand, Uganda, and the United States.
Pre-assignment details
55 participants were enrolled into Cohort 1C/1R, and 44 of these participants continued to Cohort 2. An additional 100 participants enrolled into Cohort 2. Parents/caregivers (n = 13) are not included in the participant flow result section because no baseline measurements were collected for these participants. In addition, no data collected from these participants contributed to the reporting of results for primary or secondary objectives.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1C: CAB Step 1: CAB administered orally as one 30 mg tablet once daily, beginning at the Entry visit, for 4-6 weeks.
Step 2 (Q4W dosing): CAB LA administered as three single intramuscular (IM) injections four weeks apart (600 mg injection at Week 4b, 400 mg injection at Week 8, and 400 mg injection at Week 12).
Step 2 (Q8W dosing): CAB LA administered as two single IM injections four weeks apart (600 mg injection at Week 4b and 600 mg injection at Week 8).
Oral Cabotegravir (CAB): 30 mg tablets administered orally
Long-Acting Injectable Cabotegravir (CAB LA): Administered by intramuscular (IM) injection
Combination Antiretroviral Therapy (cART): Participants will continue their pre-study cART regimen. The antiretroviral drugs in participants' cART regimens were not provided through the study. | 30 |
| Cohort 1R: RPV Step 1: RPV administered orally as one 25 mg tablet once daily, beginning at the Entry visit, for 4-6 weeks.
Step 2 (Q4W dosing): RPV LA administered as three single IM injections four weeks apart (900 mg injection at Week 4b, 600 mg injection at Week 8, 600 mg injection at and Week 12).
Step 2 (Q8W dosing): RPV LA administered as two single IM injections four weeks apart (900 mg injection at Week 4b and 900 mg injection at Week 8).
Oral Rilpivirine (RPV): 25 mg tablets administered orally
Long-Acting Injectable Rilpivirine (RPV LA): Administered by intramuscular (IM) injection
Combination Antiretroviral Therapy (cART): Participants will continue their pre-study cART regimen. The antiretroviral drugs in participants' cART regimens were not provided through the study. | 25 |
| Cohort 2A: Oral CAB + Oral RPV and CAB LA + RPV LA Step 3: CAB administered orally as one 30 mg tablet once daily AND RPV administered orally as one 25 mg tablet once daily, beginning at the Entry visit for 4-6 weeks.
Step 4: First and second injections: CAB LA administered as a 600 mg IM injection AND RPV LA administered as a 900 mg IM injection at Week 4b and at Week 8. Subsequent injections: starting at Week 16, CAB LA administered as a 600 mg IM injection AND RPV LA administered as a 900 mg IM injection every eight weeks through Week 96 or final safety extension visit.
Oral Cabotegravir (CAB): 30 mg tablets administered orally
Oral Rilpivirine (RPV): 25 mg tablets administered orally
Long-Acting Injectable Cabotegravir (CAB LA): Administered by intramuscular (IM) injection
Long-Acting Injectable Rilpivirine (RPV LA): Administered by intramuscular (IM) injection | 144 |
| Cohort 2B: CAB LA + RPV LA Step 5: First and second injections: CAB LA administered as a 600 mg IM injection AND RPV LA administered as a 900 mg IM injection at Entry and at Week 4. Subsequent injections: starting at Week 12, CAB LA administered as a 600 mg IM injection AND RPV LA administered as 900 mg IM injection every eight weeks through Week 92 or final safety extension visit.
Long-Acting Injectable Cabotegravir (CAB LA): Administered by intramuscular (IM) injection
Long-Acting Injectable Rilpivirine (RPV LA): Administered by intramuscular (IM) injection | 0 |
| Total | 199 |
Baseline characteristics
| Characteristic | Cohort 1R: RPV | Total | Cohort 1C: CAB | Cohort 2A: Oral CAB + Oral RPV and CAB LA + RPV LA | Cohort 2B: CAB LA + RPV LA |
|---|---|---|---|---|---|
| Age, Continuous Cohort 1 | 16 years | 15 years | 15 years | — | — |
| Age, Continuous Cohort 2 | — | 15 years | — | 15 years | — |
| Age, Customized Cohort 1 12 | 3 Participants | 4 Participants | 1 Participants | — | 0 Participants |
| Age, Customized Cohort 1 13 | 0 Participants | 5 Participants | 5 Participants | — | 0 Participants |
| Age, Customized Cohort 1 14 | 3 Participants | 10 Participants | 7 Participants | — | 0 Participants |
| Age, Customized Cohort 1 15 | 4 Participants | 10 Participants | 6 Participants | — | 0 Participants |
| Age, Customized Cohort 1 16 | 4 Participants | 8 Participants | 4 Participants | — | 0 Participants |
| Age, Customized Cohort 1 17 | 11 Participants | 18 Participants | 7 Participants | — | 0 Participants |
| Age, Customized Cohort 2 12 | — | 11 Participants | — | 11 Participants | — |
| Age, Customized Cohort 2 13 | — | 23 Participants | — | 23 Participants | — |
| Age, Customized Cohort 2 14 | — | 19 Participants | — | 19 Participants | — |
| Age, Customized Cohort 2 15 | — | 35 Participants | — | 35 Participants | — |
| Age, Customized Cohort 2 16 | — | 27 Participants | — | 27 Participants | — |
| Age, Customized Cohort 2 17 | — | 29 Participants | — | 29 Participants | — |
| Ethnicity (NIH/OMB) Cohort 1 Hispanic or Latino | 3 Participants | 3 Participants | 0 Participants | — | — |
| Ethnicity (NIH/OMB) Cohort 1 Not Hispanic or Latino | 22 Participants | 52 Participants | 30 Participants | — | — |
| Ethnicity (NIH/OMB) Cohort 1 Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — | — |
| Ethnicity (NIH/OMB) Cohort 2 Hispanic or Latino | — | 3 Participants | — | 3 Participants | — |
| Ethnicity (NIH/OMB) Cohort 2 Not Hispanic or Latino | — | 141 Participants | — | 141 Participants | — |
| Ethnicity (NIH/OMB) Cohort 2 Unknown or Not Reported | — | 0 Participants | — | 0 Participants | — |
| HIV-1 RNA Cohort 1 <50 copies/mL | 24 Participants | 54 Participants | 30 Participants | — | — |
| HIV-1 RNA Cohort 1 >=50 copies/mL | 1 Participants | 1 Participants | 0 Participants | — | — |
| HIV-1 RNA Cohort 2 <50 copies/mL | — | 138 Participants | — | 138 Participants | — |
| HIV-1 RNA Cohort 2 >=50 copies/mL | — | 6 Participants | — | 6 Participants | — |
| Quality of Life Dimension Scores Cohort 1 Emotional Functioning Dimension | 90 units on a scale | 90 units on a scale | 90 units on a scale | — | — |
| Quality of Life Dimension Scores Cohort 1 Physical Functioning Dimension | 100 units on a scale | 100 units on a scale | 96.9 units on a scale | — | — |
| Quality of Life Dimension Scores Cohort 1 Psychosocial Functioning Dimension | 83.3 units on a scale | 90 units on a scale | 90 units on a scale | — | — |
| Quality of Life Dimension Scores Cohort 1 School Functioning Dimension | 70 units on a scale | 80 units on a scale | 80 units on a scale | — | — |
| Quality of Life Dimension Scores Cohort 1 Social Functioning Dimension | 95 units on a scale | 100 units on a scale | 100 units on a scale | — | — |
| Quality of Life Dimension Scores Cohort 1 Total Functioning Dimension | 89.1 units on a scale | 91.3 units on a scale | 92.9 units on a scale | — | — |
| Quality of Life Dimension Scores Cohort 2 Emotional Functioning Dimension | — | 100 units on a scale | — | 100 units on a scale | — |
| Quality of Life Dimension Scores Cohort 2 Physical Functioning | — | 100 units on a scale | — | 100 units on a scale | — |
| Quality of Life Dimension Scores Cohort 2 Psychosocial Functioning | — | 91.7 units on a scale | — | 91.7 units on a scale | — |
| Quality of Life Dimension Scores Cohort 2 School Functioning Dimension | — | 80 units on a scale | — | 80 units on a scale | — |
| Quality of Life Dimension Scores Cohort 2 Social Functioning Dimension | — | 100 units on a scale | — | 100 units on a scale | — |
| Quality of Life Dimension Scores Cohort 2 Total Functioning | — | 94.6 units on a scale | — | 94.6 units on a scale | — |
| Race (NIH/OMB) Cohort 1 American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 1 Asian | 0 Participants | 9 Participants | 9 Participants | — | — |
| Race (NIH/OMB) Cohort 1 Black or African American | 21 Participants | 42 Participants | 21 Participants | — | — |
| Race (NIH/OMB) Cohort 1 More than one race | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 1 Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 1 Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 1 White | 4 Participants | 4 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Cohort 2 American Indian or Alaska Native | — | 0 Participants | — | 0 Participants | — |
| Race (NIH/OMB) Cohort 2 Asian | — | 36 Participants | — | 36 Participants | — |
| Race (NIH/OMB) Cohort 2 Black or African American | — | 106 Participants | — | 106 Participants | — |
| Race (NIH/OMB) Cohort 2 More than one race | — | 0 Participants | — | 0 Participants | — |
| Race (NIH/OMB) Cohort 2 Native Hawaiian or Other Pacific Islander | — | 0 Participants | — | 0 Participants | — |
| Race (NIH/OMB) Cohort 2 Unknown or Not Reported | — | 0 Participants | — | 0 Participants | — |
| Race (NIH/OMB) Cohort 2 White | — | 2 Participants | — | 2 Participants | — |
| Region of Enrollment, Customized Cohort 1 Botswana | 5 Participants | 5 Participants | 0 Participants | — | — |
| Region of Enrollment, Customized Cohort 1 South Africa | 3 Participants | 17 Participants | 14 Participants | — | — |
| Region of Enrollment, Customized Cohort 1 Thailand | 0 Participants | 8 Participants | 8 Participants | — | — |
| Region of Enrollment, Customized Cohort 1 Uganda | 0 Participants | 0 Participants | 0 Participants | — | — |
| Region of Enrollment, Customized Cohort 1 United States | 17 Participants | 25 Participants | 8 Participants | — | — |
| Region of Enrollment, Customized Cohort 2 Botswana | — | 25 Participants | — | 25 Participants | — |
| Region of Enrollment, Customized Cohort 2 South Africa | — | 43 Participants | — | 43 Participants | — |
| Region of Enrollment, Customized Cohort 2 Thailand | — | 36 Participants | — | 36 Participants | — |
| Region of Enrollment, Customized Cohort 2 Uganda | — | 20 Participants | — | 20 Participants | — |
| Region of Enrollment, Customized Cohort 2 United States | — | 20 Participants | — | 20 Participants | — |
| Sex: Female, Male Cohort 1 Female | 12 Participants | 26 Participants | 14 Participants | — | — |
| Sex: Female, Male Cohort 1 Male | 13 Participants | 29 Participants | 16 Participants | — | — |
| Sex: Female, Male Cohort 2 Female | — | 74 Participants | — | 74 Participants | — |
| Sex: Female, Male Cohort 2 Male | — | 70 Participants | — | 70 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 25 | 0 / 144 |
| other Total, other adverse events | 28 / 30 | 23 / 25 | 136 / 144 |
| serious Total, serious adverse events | 1 / 30 | 0 / 25 | 9 / 144 |
Outcome results
Primary
Apparent Total Body Clearance (CL/F) of Step 1 Oral CAB (Cohort 1C)
We present the geometric mean of the total body clearance of CAB and associated geometric coefficient of variation, based on analysis of intensive pharmacokinetic (PK) samples.
Time frame: Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8 and (for Q4W dosing) 24 hours post-dose
Population: Cohort 1 All Treated: Cohort 1 participants who have taken at least 1 dose of any study product on Cohort 1 and have an available total body clearance measurement
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Apparent Total Body Clearance (CL/F) of Step 1 Oral CAB (Cohort 1C) | 216.0 mL/h | Geometric Coefficient of Variation 59.1 |
Primary
Geometric Mean Area Under the Plasma Concentration-time Curve (AUC) for Step 1 Oral CAB (Cohort 1C)
AUC calculated using non-compartmental methods with linear up-log down trapezoidal rule (Phoenix WinNonlin v 8.3, Certara®). We present the geometric mean of the AUC with associated geometric coefficient of variation.
Time frame: Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8, and (for Q4W dosing) 24 hours post-dose
Population: Cohort 1 All Treated: Cohort 1 participants who have taken at least 1 dose of any study product on Cohort 1 and had an available AUC measurement
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Area Under the Plasma Concentration-time Curve (AUC) for Step 1 Oral CAB (Cohort 1C) | 139 (h*ug)/mL | Geometric Coefficient of Variation 59.1 |
Primary
Geometric Mean Concentration of LA CAB/LA RPV at Week 16 (Cohort 1 Q4W)
We present the geometric mean concentration of LA CAB/LA RPV and associated geometric coefficients of variation for participants on the Q4W dosing regimen, based on analysis of pre-dose PK sample.
Time frame: Week 16
Population: Cohort 1 Q4W: Cohort 1 participants who received the Q4W dosing regimen on Cohort 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Concentration of LA CAB/LA RPV at Week 16 (Cohort 1 Q4W) | 2.91 ug/mL | Geometric Coefficient of Variation 58.8 |
| Cohort 1R: RPV | Geometric Mean Concentration of LA CAB/LA RPV at Week 16 (Cohort 1 Q4W) | 0.0644 ug/mL | Geometric Coefficient of Variation 59.9 |
Primary
Geometric Mean Concentration of LA CAB/LA RPV at Week 16 (Cohort 1 Q8W)
We present the geometric mean concentration of LA CAB/LA RPV and associated geometric coefficients of variation for participants on the Q4W dosing regimen, based on analysis of the pre-dose PK sample.
Time frame: Week 16
Population: Cohort 1 participants who received the Q8W dosing regimen on Cohort 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Concentration of LA CAB/LA RPV at Week 16 (Cohort 1 Q8W) | 1.01 ug/mL | Geometric Coefficient of Variation 237 |
| Cohort 1R: RPV | Geometric Mean Concentration of LA CAB/LA RPV at Week 16 (Cohort 1 Q8W) | 0.0449 ug/mL | Geometric Coefficient of Variation 38.2 |
Primary
Geometric Mean Maximum Plasma Concentration (Cmax) of LA CAB/LA RPV (Cohort 1 Q4W)
We present the geometric mean of the maximum plasma concentration of LA CAB/LA RPV and associated geometric coefficient of variation for the first injection in participants on the Q4W dosing regimen, based on analysis of intensive PK samples.
Time frame: Samples collected at Weeks 4b, 5, 6, and 8
Population: Cohort 1 Q4W: Cohort 1 participants who received the Q4W dosing regimen on Cohort 1
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Maximum Plasma Concentration (Cmax) of LA CAB/LA RPV (Cohort 1 Q4W) | 9.56 ug/mL | Geometric Coefficient of Variation 32.2 |
| Cohort 1R: RPV | Geometric Mean Maximum Plasma Concentration (Cmax) of LA CAB/LA RPV (Cohort 1 Q4W) | 0.132 ug/mL | Geometric Coefficient of Variation 35.5 |
Primary
Geometric Mean Maximum Plasma Concentration (Cmax) of LA CAB/LA RPV (Cohort 1 Q8W)
We present the geometric mean of the maximum plasma concentration of LA CAB/LA RPV and associated geometric coefficient of variation for the first injection in participants on the Q8W dosing regimen, based on analysis of intensive PK samples.
Time frame: Samples collected at Weeks 4b, 5, and 8
Population: Cohort 1 participants who received the Q8W dosing regimen on Cohort 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Maximum Plasma Concentration (Cmax) of LA CAB/LA RPV (Cohort 1 Q8W) | 6.42 ug/mL | Geometric Coefficient of Variation 42.2 |
| Cohort 1R: RPV | Geometric Mean Maximum Plasma Concentration (Cmax) of LA CAB/LA RPV (Cohort 1 Q8W) | 0.129 ug/mL | Geometric Coefficient of Variation 39.4 |
Primary
Geometric Mean Maximum Plasma Concentration (Cmax) of Oral CAB (Cohort 1C)
We present the geometric mean of the maximum plasma concentration of CAB and associated geometric coefficient of variation, based on analysis of intensive PK samples
Time frame: Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8 and (for Q4W dosing) 24 hours post-dose
Population: Cohort 1 All Treated: Cohort 1 participants who have taken at least 1 dose of any study product on Cohort 1 with an available Cmax measurement
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Maximum Plasma Concentration (Cmax) of Oral CAB (Cohort 1C) | 8.90 ug/mL | Geometric Coefficient of Variation 43.1 |
Primary
Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q4W)
We present the geometric mean pre-dose concentrations of each injection and associated geometric coefficient of variation for participants on the Q4W dosing regimen, based on analysis of pre-dose PK samples.
Time frame: Week 4b, Week 8, Week 12
Population: Cohort 1 participants who received the Q4W dosing regimen on Cohort 1.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q4W) | Week 4b | 5.46 ug/mL | Geometric Coefficient of Variation 39.6 |
| Cohort 1C: CAB | Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q4W) | Week 8 | 2.10 ug/mL | Geometric Coefficient of Variation 37 |
| Cohort 1C: CAB | Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q4W) | Week 12 | 2.73 ug/mL | Geometric Coefficient of Variation 76.7 |
| Cohort 1R: RPV | Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q4W) | Week 4b | 0.0704 ug/mL | Geometric Coefficient of Variation 227 |
| Cohort 1R: RPV | Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q4W) | Week 8 | 0.0441 ug/mL | Geometric Coefficient of Variation 75.9 |
| Cohort 1R: RPV | Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q4W) | Week 12 | 0.0555 ug/mL | Geometric Coefficient of Variation 56.7 |
Primary
Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q8W)
We present the geometric mean pre-dose concentration of the first injection and associated geometric coefficient of variation for participants on the Q4W dosing regimen, based on analysis of pre-dose PK samples.
Time frame: Week 4b, Week 8
Population: We present the geometric mean pre-dose concentration of the first injection and associated coefficient of variation for participants on the Q4W dosing regimen, based on analysis of intensive PK samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q8W) | Week 8 | 1.33 ug/mL | Geometric Coefficient of Variation 105 |
| Cohort 1C: CAB | Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q8W) | Week 4b | 2.89 ug/mL | Geometric Coefficient of Variation 194 |
| Cohort 1R: RPV | Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q8W) | Week 4b | 0.0703 ug/mL | Geometric Coefficient of Variation 24.8 |
| Cohort 1R: RPV | Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q8W) | Week 8 | 0.0327 ug/mL | Geometric Coefficient of Variation 28.8 |
Primary
Geometric Mean Pre-dose Concentration (C0) of Oral CAB (Cohort 1C)
We present the geometric mean pre-dose CAB concentration and associated geometric coefficient of variation, based on analysis of intensive PK samples.
Time frame: Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8, and (for Q4W dosing) 24 hours post-dose
Population: Cohort 1 All Treated: Cohort 1 participants who have taken at least 1 dose of any study product on Cohort 1 with an available pre-dose concentration measurement
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Pre-dose Concentration (C0) of Oral CAB (Cohort 1C) | 4.09 ug/mL | Geometric Coefficient of Variation 96.1 |
Primary
Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1)
We present the proportion of participants who died due to adverse events assessed as related to study product by the site investigator of record through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 1 Treatment Initiation through Week 16
Population: Cohort 1 Evaluable: Cohort 1 participants who were treated exclusively on the dose being evaluated for a given cohort, and either (1) completed all treatment regimen through Cohort 1 Week 16 and completed the Week 16 visit or (2) experienced any of the following: death attributable to the study product; study product-related Grade 3 or higher event (excluding injection site adverse events); OR permanently discontinued from treatment due to study product-related toxicity (regardless of grade)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1) | 0 proportion of participants |
| Cohort 1R: RPV | Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1) | 0 proportion of participants |
Primary
Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1)
We present the proportion of participants who died due to adverse events assessed as related to study product by the site investigator of record through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 1 Treatment Initiation through Week 4
Population: Cohort 1 Evaluable: Cohort 1 participants who were treated exclusively on the dose being evaluated for a given cohort, and either (1) completed all treatment regimen through Cohort 1 Week 4 and completed the Week 4 visit or (2) experienced any of the following: death attributable to the study product; study product-related Grade 3 or higher event (excluding injection site adverse events); OR permanently discontinued from treatment due to study product-related toxicity (regardless of grade)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1) | 0 proportion of participants |
Primary
Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2)
We present the proportion of participants who died due to adverse events assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 2 Treatment Initiation through Week 24
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 24 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the dose-finding period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2) | 0 proportion of participants |
Primary
Proportion of Participants Who Had Grade 3 or Higher Adverse Event (Cohort 1)
Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 1 Treatment Initiation through Week 4
Population: Cohort 1 Evaluable: Cohort 1 participants who were treated exclusively on the dose being evaluated for a given cohort, and either (1) completed all treatment regimen through Cohort 1 Week 4 and completed the Week 4 visit or (2) experienced any of the following: death attributable to the study product; study product-related Grade 3 or higher event (excluding injection site adverse events); OR permanently discontinued from treatment due to study product-related toxicity (regardless of grade).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Grade 3 or Higher Adverse Event (Cohort 1) | 0 proportion of participants |
Primary
Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 1)
Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE assessed as related to study product by the site investigator of record through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 1 Treatment Initiation through Week 16
Population: Cohort 1 Evaluable: Cohort 1 participants who were treated exclusively on the dose being evaluated for a given cohort, and either (1) completed all treatment regimen through Cohort 1 Week 16 and completed the Week 16 visit or (2) experienced any of the following: death attributable to the study product; study product-related Grade 3 or higher event (excluding injection site adverse events); OR permanently discontinued from treatment due to study product-related toxicity (regardless of grade)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 1) | 0.035 proportion of participants |
| Cohort 1R: RPV | Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 1) | 0.04 proportion of participants |
Primary
Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 1)
Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE assessed as related by the site investigator of record to study product through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 1 Treatment Initiation through Week 4
Population: Cohort 1 Evaluable: Cohort 1 participants who were treated exclusively on the dose being evaluated for a given cohort, and either (1) completed all treatment regimen through Cohort 1 Week 4 and completed the Week 4 visit or (2) experienced any of the following: death attributable to the study product; study product-related Grade 3 or higher event (excluding injection site adverse events); OR permanently discontinued from treatment due to study product-related toxicity (regardless of grade)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 1) | 0 proportion of participants |
Primary
Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 2)
Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 2 Treatment Initiation through Week 24
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 24 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the dose-finding period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 2) | 0 proportion of participants |
Primary
Proportion of Participants Who Had Grade 3 or Higher Adverse Events (Cohort 1)
Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 1 Treatment Initiation through Week 16
Population: Cohort 1 Evaluable: Cohort 1 participants who were treated exclusively on the dose being evaluated for a given cohort, and either (1) completed all treatment regimen through Cohort 1 Week 16 and completed the Week 16 visit or (2) experienced any of the following: death attributable to the study product; study product-related Grade 3 or higher event (excluding injection site adverse events); OR permanently discontinued from treatment due to study product-related toxicity (regardless of grade)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Grade 3 or Higher Adverse Events (Cohort 1) | 0.24 proportion of participants |
| Cohort 1R: RPV | Proportion of Participants Who Had Grade 3 or Higher Adverse Events (Cohort 1) | 0.22 proportion of participants |
Primary
Proportion of Participants Who Had Grade 3 or Higher Adverse Events (Cohort 2)
Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 2 Treatment Initiation through Week 24
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 24 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the dose-finding period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Grade 3 or Higher Adverse Events (Cohort 2) | 0.10 proportion of participants |
Primary
Proportion of Participants Who Had Serious Adverse Events Meeting ICH Criteria Assessed as Related to Study Product/s (Cohort 2)
Adverse events (AE) were assessed as a Serious AE by ICH criteria. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details). We present the proportion of participants with at least one serious AE assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 2 Treatment Initiation through Week 24
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 24 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the dose-finding period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Serious Adverse Events Meeting ICH Criteria Assessed as Related to Study Product/s (Cohort 2) | 0 proportion of participants |
Primary
Proportion of Participants Who Had Serious Adverse Events Meeting International Conference on Harmonisation (ICH) Criteria Assessed as Related to Study Product/s (Cohort 1)
Adverse events (AE) were assessed as a Serious AE by ICH criteria. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details). We present the proportion of participants with at least one serious AE assessed as related to study product by the site investigator of record through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 1 Treatment Initiation through Week 4
Population: Cohort 1 Evaluable: Cohort 1 participants who were treated exclusively on the dose being evaluated for a given cohort, and either (1) completed all treatment regimen through Cohort 1 Week 4 and completed the Week 4 visit or (2) experienced any of the following: death attributable to the study product; study product-related Grade 3 or higher event (excluding injection site adverse events); OR permanently discontinued from treatment due to study product-related toxicity (regardless of grade).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Serious Adverse Events Meeting International Conference on Harmonisation (ICH) Criteria Assessed as Related to Study Product/s (Cohort 1) | 0 proportion of participants |
Primary
Proportion of Participants Who Had Serious Adverse Events Meeting International Conference on Harmonisation (ICH) Criteria Assessed as Related to Study Product/s (Cohort 1)
Adverse events (AE) were assessed as a Serious AE by ICH criteria. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details). We present the proportion of participants with at least one serious AE assessed as related to study product by the site investigator of record through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 1 Treatment Initiation through Week 16
Population: Cohort 1 Evaluable: Cohort 1 participants who were treated exclusively on the dose being evaluated for a given cohort, and either (1) completed all treatment regimen through Cohort 1 Week 16 and completed the Week 16 visit or (2) experienced any of the following: death attributable to the study product; study product-related Grade 3 or higher event (excluding injection site adverse events); OR permanently discontinued from treatment due to study product-related toxicity (regardless of grade)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Serious Adverse Events Meeting International Conference on Harmonisation (ICH) Criteria Assessed as Related to Study Product/s (Cohort 1) | 0 proportion of participants |
| Cohort 1R: RPV | Proportion of Participants Who Had Serious Adverse Events Meeting International Conference on Harmonisation (ICH) Criteria Assessed as Related to Study Product/s (Cohort 1) | 0 proportion of participants |
Primary
Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1)
We present the proportion of participants who permanently discontinued study product due to adverse events (AEs) assessed as related to study product by the site investigator of record through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 1 Treatment Initiation through Week 16
Population: Cohort 1 Evaluable: Cohort 1 participants who were treated exclusively on the dose being evaluated for a given cohort, and either (1) completed all treatment regimen through Cohort 1 Week 16 and completed the Week 16 visit or (2) experienced any of the following: death attributable to the study product; study product-related Grade 3 or higher event (excluding injection site adverse events); OR permanently discontinued from treatment due to study product-related toxicity (regardless of grade)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1) | 0 proportion of participants |
| Cohort 1R: RPV | Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1) | 0.044 proportion of participants |
Primary
Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1)
We present the proportion of participants who permanently discontinued study product due to adverse events (AEs) assessed as related to study product by the site investigator of record through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 1 Treatment Initiation through Week 4
Population: Cohort 1 Evaluable: Cohort 1 participants who were treated exclusively on the dose being evaluated for a given cohort, and either (1) completed all treatment regimen through Cohort 1 Week 4 and completed the Week 4 visit or (2) experienced any of the following: death attributable to the study product; study product-related Grade 3 or higher event (excluding injection site adverse events); OR permanently discontinued from treatment due to study product-related toxicity (regardless of grade)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1) | 0 proportion of participants |
Primary
Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2)
We present the proportion of participants who permanently discontinued study product due to adverse events (AEs) assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 2 Treatment Initiation through Week 24
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 24 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the dose-finding period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2) | 0 proportion of participants |
Primary
Time of Maximum Concentration (Tmax) of LA CAB/LA RPV (Cohort 1 Q4W)
We present the mean time of maximum concentration of LA CAB/LA RPV at the first injection and associated standard deviation for participants on the Q4W dosing regimen, based on analysis of intensive PK samples.
Time frame: Samples collected at Weeks 4b, 5, 6, 8
Population: Cohort 1 participants who received the Q4W dosing regimen on Cohort 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Time of Maximum Concentration (Tmax) of LA CAB/LA RPV (Cohort 1 Q4W) | 1.50 h | Standard Deviation 0.551 |
| Cohort 1R: RPV | Time of Maximum Concentration (Tmax) of LA CAB/LA RPV (Cohort 1 Q4W) | 89.6 h | Standard Deviation 162 |
Primary
Time of Maximum Concentration (Tmax) of LA CAB/LA RPV (Cohort 1 Q8W)
We present the mean time of maximum concentration of LA CAB/LA RPV at the first injection and associated standard deviation for participants on the Q8W dosing regimen, based on analysis of intensive PK samples.
Time frame: Samples collected at Weeks 4b, 5, and 8
Population: Cohort 1 participants who received the Q8W dosing regimen on Cohort 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Time of Maximum Concentration (Tmax) of LA CAB/LA RPV (Cohort 1 Q8W) | 1.84 h | Standard Deviation 0.829 |
| Cohort 1R: RPV | Time of Maximum Concentration (Tmax) of LA CAB/LA RPV (Cohort 1 Q8W) | 18.6 h | Standard Deviation 53.5 |
Primary
Time of Maximum Concentration (Tmax) of Oral CAB (Cohort 1C)
We present the mean time of maximum concentration of CAB and associated standard deviation, based on analysis of intensive PK samples.
Time frame: Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8, and (for Q4W dosing) 24 hours post-dose
Population: Cohort 1 All Treated: Cohort 1 participants who have taken at least 1 dose of any study product on Cohort 1 with an available Tmax measurement
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1C: CAB | Time of Maximum Concentration (Tmax) of Oral CAB (Cohort 1C) | 2.73 h | Standard Deviation 1.13 |
Secondary
Geometric Mean Pre-dose Concentration (C0) of Oral CAB (Cohort 2)
We present the geometric mean of the pre-dose concentration of oral CAB and oral RPV and associated coefficient of variation, based on analysis of pre-dose PK sample.
Time frame: Week 2
Population: Cohort 2 All Treated: Cohort 2 participants who have taken at least 1 dose of any study product on Cohort 2
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Pre-dose Concentration (C0) of Oral CAB (Cohort 2) | CAB concentration | 6.65 ug/mL | Geometric Coefficient of Variation 42.3 |
| Cohort 1C: CAB | Geometric Mean Pre-dose Concentration (C0) of Oral CAB (Cohort 2) | RPV concentration | 0.0708 ug/mL | Geometric Coefficient of Variation 59 |
Secondary
Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 24: Pre-dose CAB and RPV Concentrations at Week 16 (Cohort 2)
We present the geometric mean of the ratios of pre-dose CAB and RPV concentrations at Week 24:Week 16 and associated coefficient of variation, based on analysis of pre-dose PK samples.
Time frame: Week 16 and Week 24
Population: Cohort 2 All Treated: Cohort 2 participants who have taken at least 1 dose of any study product on Cohort 2
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 24: Pre-dose CAB and RPV Concentrations at Week 16 (Cohort 2) | CAB Ratio | 0.974 ratio | Geometric Coefficient of Variation 47 |
| Cohort 1C: CAB | Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 24: Pre-dose CAB and RPV Concentrations at Week 16 (Cohort 2) | RPV Ratio | 1.22 ratio | Geometric Coefficient of Variation 32.7 |
Secondary
Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 24: Pre-dose CAB and RPV Concentrations at Week 8 (Cohort 2)
We present the geometric mean of the ratios of pre-dose CAB and RPV concentrations at Week 24:Week 8 and associated coefficient of variation, based on analysis of pre-dose PK samples.
Time frame: Week 8 and Week 24
Population: Cohort 2 All Treated: Cohort 2 participants who have taken at least 1 dose of any study product on Cohort 2
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 24: Pre-dose CAB and RPV Concentrations at Week 8 (Cohort 2) | CAB Ratio | 1.14 ratio | Geometric Coefficient of Variation 107 |
| Cohort 1C: CAB | Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 24: Pre-dose CAB and RPV Concentrations at Week 8 (Cohort 2) | RPV Ratio | 1.35 ratio | Geometric Coefficient of Variation 47.1 |
Secondary
Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 48: Pre-dose CAB and RPV Concentrations at Week 16 (Cohort 2)
We present the geometric mean of the ratios of pre-dose CAB and RPV concentrations at Week 48:Week 16 and associated coefficient of variation, based on analysis of pre-dose PK samples.
Time frame: Week 16 and Week 48
Population: Cohort 2 All Treated: Cohort 2 participants who have taken at least 1 dose of any study product on Cohort 2
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 48: Pre-dose CAB and RPV Concentrations at Week 16 (Cohort 2) | CAB Ratio | 1.12 ratio | Geometric Coefficient of Variation 50.9 |
| Cohort 1C: CAB | Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 48: Pre-dose CAB and RPV Concentrations at Week 16 (Cohort 2) | RPV Ratio | 1.68 ratio | Geometric Coefficient of Variation 37.9 |
Secondary
Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 48: Pre-dose CAB and RPV Concentrations at Week 8 (Cohort 2)
We present the geometric mean of the ratios of pre-dose CAB and RPV concentrations at Week 48:Week 8 and associated coefficient of variation, based on analysis of pre-dose PK samples.
Time frame: Week 8 and Week 48
Population: Cohort 2 All Treated: Cohort 2 participants who have taken at least 1 dose of any study product on Cohort 2
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1C: CAB | Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 48: Pre-dose CAB and RPV Concentrations at Week 8 (Cohort 2) | CAB Ratio | 1.31 ratio | Geometric Coefficient of Variation 97.6 |
| Cohort 1C: CAB | Geometric Mean Ratio of Pre-dose CAB and RPV Concentrations at Week 48: Pre-dose CAB and RPV Concentrations at Week 8 (Cohort 2) | RPV Ratio | 1.84 ratio | Geometric Coefficient of Variation 47.1 |
Secondary
Median Dimension of Quality of Life Scores
A commonly used 23-item Pediatric Quality of Life Inventory, the PedsQLTM, was used to measure physical, emotional, and social dimensions of health as well as school functioning. Question responses were used to generate scores from 0-100 (100 being the best quality of life) based on the PedsQLTM guidelines. The number of participants drops slightly for the school functioning result as not all participants are eligible to answer these school-related questions.
Time frame: Week 16
Population: Cohort 1 All Treated: Cohort 1 participants who have taken at least 1 dose of any study product on Cohort 1
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1C: CAB | Median Dimension of Quality of Life Scores | Physical Functioning | 96.9 score on a scale |
| Cohort 1C: CAB | Median Dimension of Quality of Life Scores | Emotional Functioning | 95 score on a scale |
| Cohort 1C: CAB | Median Dimension of Quality of Life Scores | Social Functioning | 100 score on a scale |
| Cohort 1C: CAB | Median Dimension of Quality of Life Scores | School Functioning | 80 score on a scale |
| Cohort 1C: CAB | Median Dimension of Quality of Life Scores | Psychosocial Functioning | 91.7 score on a scale |
| Cohort 1C: CAB | Median Dimension of Quality of Life Scores | Total Functioning | 93.5 score on a scale |
| Cohort 1R: RPV | Median Dimension of Quality of Life Scores | Psychosocial Functioning | 91.7 score on a scale |
| Cohort 1R: RPV | Median Dimension of Quality of Life Scores | Physical Functioning | 100 score on a scale |
| Cohort 1R: RPV | Median Dimension of Quality of Life Scores | School Functioning | 85 score on a scale |
| Cohort 1R: RPV | Median Dimension of Quality of Life Scores | Emotional Functioning | 95 score on a scale |
| Cohort 1R: RPV | Median Dimension of Quality of Life Scores | Total Functioning | 94.6 score on a scale |
| Cohort 1R: RPV | Median Dimension of Quality of Life Scores | Social Functioning | 100 score on a scale |
Secondary
Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2)
We present the proportion of participants who died due to adverse events assessed as related to study product by the site investigator of record through 48 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 2 treatment initiation through Week 48
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 48 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2) | 0 proportion of participants |
Secondary
Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 2)
Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE assessed as related to study product by the site investigator of record through 48 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 2 treatment initiation through Week 48
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 48 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Grade 3 or Higher Adverse Events Assessed as Related to Study Product/s (Cohort 2) | 0.02 proportion of participants |
Secondary
Proportion of Participants Who Had Grade 3 or Higher Adverse Events (Cohort 2)
Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 48 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 2 treatment initiation through Week 48
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 48 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Grade 3 or Higher Adverse Events (Cohort 2) | 0.14 proportion of participants |
Secondary
Proportion of Participants Who Had Serious Adverse Events Meeting ICH Criteria, as Cited in References, Assessed as Related to Study Product/s (Cohort 2)
Adverse events (AE) were assessed as a Serious AE by ICH criteria. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details). We present the proportion of participants with at least one serious AE assessed as related to study product by the site investigator of record through 48 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 2 treatment initiation through Week 48
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 48 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Had Serious Adverse Events Meeting ICH Criteria, as Cited in References, Assessed as Related to Study Product/s (Cohort 2) | 0 proportion of participants |
Secondary
Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2)
We present the proportion of participants who permanently discontinued study product due to adverse events (AEs) assessed as related to study product by the site investigator of record through 48 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).
Time frame: Cohort 2 treatment initiation through Week 48
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 48 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the treatment period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2) | 0 proportion of participants |
Secondary
Proportion of Participants Who Reported Hurts Whole Lot or Hurts Worst in Regards to Being Bothered by Pain During Injection of CAB LA or RPV LA (Cohort 1)
Results collected via administration of Pain During Injection survey to participants after receiving injection. Pain during injections was assessed using the Faces Pain Scale-Revised which includes 6 visual and text options: no hurt, hurts little bit, hurts little more, hurts even more, hurts whole lot and hurts worst.
Time frame: Week 8
Population: Cohort 1 All Treated: Cohort 1 participants who have taken at least 1 dose of any study product on Cohort 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants Who Reported Hurts Whole Lot or Hurts Worst in Regards to Being Bothered by Pain During Injection of CAB LA or RPV LA (Cohort 1) | 0 proportion of participants |
| Cohort 1R: RPV | Proportion of Participants Who Reported Hurts Whole Lot or Hurts Worst in Regards to Being Bothered by Pain During Injection of CAB LA or RPV LA (Cohort 1) | 0.043 proportion of participants |
Secondary
Proportion of Participants With HIV-1 RNA < 50 Copies/mL (Cohort 1)
We present the proportion of participants with results of HIV-1 RNA \< 50 copies/mL at Week 16
Time frame: Week 16
Population: Cohort 1 All Treated: Cohort 1 participants who have taken at least 1 dose of any study product on Cohort 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants With HIV-1 RNA < 50 Copies/mL (Cohort 1) | 0.964 proportion of participants |
| Cohort 1R: RPV | Proportion of Participants With HIV-1 RNA < 50 Copies/mL (Cohort 1) | 1.00 proportion of participants |
Secondary
Proportion of Participants With Plasma HIV-1 RNA >= 200 Copies/mL Per the FDA Snapshot (Cohort 2)
We present the proportion of participants with HIV-1 RNA \>= 200 copies/mL and associated exact 95% CI (Clopper-Pearson) per the FDA snapshot, based on laboratory evaluations.
Time frame: Week 48
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 48 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the treatment period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants With Plasma HIV-1 RNA >= 200 Copies/mL Per the FDA Snapshot (Cohort 2) | 0 proportion of participants |
Secondary
Proportion of Participants With Plasma HIV-1 RNA >= 200 Copies/mL Per the FDA Snapshot (Cohort 2)
We present the proportion of participants with HIV-1 RNA \>= 200 copies/mL and associated exact 95% CI (Clopper-Pearson) per the FDA snapshot, based on laboratory evaluations.
Time frame: Week 24
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 24 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the treatment period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants With Plasma HIV-1 RNA >= 200 Copies/mL Per the FDA Snapshot (Cohort 2) | 0 proportion of participants |
Secondary
Proportion of Participants With Plasma HIV-1 RNA >= 50 Copies/mL Per the FDA Snapshot (Cohort 2)
We present the proportion of participants with HIV-1 RNA \>= 50 copies/mL and associated exact 95% CI (Clopper-Pearson) per the FDA snapshot, based on laboratory evaluations.
Time frame: Week 48
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 48 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the treatment period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants With Plasma HIV-1 RNA >= 50 Copies/mL Per the FDA Snapshot (Cohort 2) | 0 proportion of participants |
Secondary
Proportion of Participants With Plasma HIV-1 RNA >= 50 Copies/mL Per the FDA Snapshot (Cohort 2)
We present the proportion of participants with HIV-1 RNA \>= 50 copies/mL and associated exact 95% CI (Clopper-Pearson) per the FDA snapshot, based on laboratory evaluations.
Time frame: Week 24
Population: Cohort 2 Naive Evaluable: Cohort 2 participants who did not participate in Cohort 1, were treated exclusively on the final recommended dose for Cohort 2, and either (1) completed all treatment regimens through Week 24 visit or (2) experienced any of the following: death attributable to the study product(s); study product(s)-related Grade 3 or higher event (excluding ISR AEs); OR permanently discontinued from treatment due to study product(s)-related toxicity during the treatment period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1C: CAB | Proportion of Participants With Plasma HIV-1 RNA >= 50 Copies/mL Per the FDA Snapshot (Cohort 2) | 0.02 proportion of participants |